Melanoma is the fastest growing cancer in the United States and worldwide. Advanced stages of the disease are deadly with metastatic melanoma patients having a median lifespan of less than one year. Most melanomas are characterized by an upregulation of the mitogen activated protein kinase (MAPK) pathway with approximately 50 to 70% of patients harboring the V600E mutation to BRaf. New treatments inhibiting BRaf or its direct target MEK1/2 proteins have recently been developed and have shown promising results in clinical trials. Regrettably, these initial results have proven to be short lived with resistanc to the new therapeutic agent quickly taking hold. Since then, identifying the mechanisms of resistance to these kinase inhibitors has become an active area of research. The objective of this study is to determine if substrate selective inhibition of the extracellular signal-regulated kinase (ERK) proteins can overcome some of the mechanisms of resistance that have been identified. Specifically, proposed studies will test the hypothesis that ERK inhibitors can overcome resistance induced by mutations that occur in MEK1 as well as overexpression of mitogen activated protein kinase kinase kinase 8 (MAP3K8 or COT). The outcome of this study is expected to provide the framework around which future clinical trials can test the efficacy of ERK-targeted inhibitors in patients who have developed resistance to current therapies targeting BRaf and MEK proteins.